1. Field of the Invention
The present invention relates generally to methods of hemofiltration. More specifically, the present invention relates to a novel method of hemofiltration for toxic mediator-related diseases.
2. Description of the Related Art
Medical illness, trauma, complication of surgery, i.e., any human disease state, if sufficiently injurious to the patient, may elicit the Systemic Inflammatory Response Syndrome (SIRS). SIRS within physiologic limits is beneficial, i.e., promoting removal of dead tissue, healing of injured tissue and mobilization of host defenses to resist or combat infection. If the stimulus to SIRS is too potent, e.g., as a result of massive tissue injury or microbial sepsis, then the SIRS may be extreme. The resulting excessive inflammation is injurious or destructive to vital organ tissue resulting in vital organ dysfunction or failure. This is recognized clinically as multi-organ system failure (MOSF). Depending on the number of organ systems failing, MOSF has a mortality rate of 40-100%. In the USA each year, MOSF results in about 150,000 deaths, afflicts 400-600,000 patients, and adds billions of dollars of cost to the nation's health care.
Critical care medicine techniques available to manage SIRS-MOSF are entirely supportive. There is no definitive therapy. The mechanism of SIRS is the excessive release of host derived inflammatory mediators, referred to in this context as toxic mediators (TM). TM include various cytokines (tumor necrosis factor, TNF; the interleukins; interferon), various prostaglandins (PG I.sub.2, E.sub.2, Leukotrienes), various clotting factors (platelet activating factor, PAF), various peptidases, reactive oxygen metabolites, and various poorly understood peptides which cause organ dysfunction (myocardial depressant factor, MDF). These compounds interact in a cascade fashion with many augmenting the inflammatory response. Some are directly injurious to tissue (MDF, peptidases), others promote destructive inflammation (cytokines). Infection (abscesses, sepsis) is a common complication of critical illness. Certain bacterial exotoxins, endotoxins or enterotoxins are extremely potent stimuli to SIRS. Sepsis is the single most common cause of SIRS leading to MOSF. The development and use of effective antibiotics and other supportive measures have had no effect on the death rate from MOSF.
Hemofiltration (HF) was developed as a technique to control overhydration and acute renal failure in unstable intensive care unit (ICU) patients. The technique of HF involves a hemofilter. The hemofilter consists of a woven membrane (polysulfone, polyamide, etc.) fabricated as either a parallel plate or hollow fiber filtering surface. The blood path to, through, and from the membrane is low resistance so the patients' own blood pressure drives blood through the filter circuit. The pores of most filter membranes will allow passage of molecules up to 30,000 Daltons with very few membranes allowing passage of molecules up to 50,000 Daltons. The membranes were built to achieve the following specific goals. First, to permit high conductance of the aqueous phase of blood plasma water needed to permit the formation of ultrafiltrate at a fairly low transmembrane pressure (typically 20-40 mm Hg). This requires a relatively large pore size which incidentally passes molecules of up to 30,000 to 50,000 Daltons. The ultrafiltrate, with current filters, contains electrolytes and small molecules (urea, creatinine, uric acid) but no cells and proteins. The composition of the ultrafiltrate is very similar to plasma water. Second, prior art membranes were designed specifically to avoid passage of albumin (68,000 Daltons). Loss of albumin, and subsequently, oncotic pressure, could cause or aggravate tissue edema and organ dysfunction (e.g., pulmonary edema).
During filtration of protein containing solutions, colloids or suspensions, the accumulation of protein as a gel or polarization layer occurs on the membrane surface. This gel layer typically reduces effective pore size, reducing the filterable molecular weights by roughly 10-40%. Therefore, pore sizes selected are somewhat larger than needed, anticipating a reduction in effective size. Thus, present membranes allow filtration and removal of excess water, electrolytes, small molecules and nitrogenous waste while avoiding any loss of albumin or larger proteins. These membranes are well-suited to their accepted uses, that is, treatment of overhydration and acute renal failure.
The hemofilter is part of a blood circuit. In passive flow HF, arterial blood flows through a large bore cannula, into plastic tubing leading to the filter; blood returns from the filter through plastic tubing to a vein. This is known as arteriovenous HF. Alternately, a blood pump is used so that blood is pumped from a vein to the filter and returned to a vein or venovenous HF. Ultrafiltrate collects in the filter jacket and is drained through the ultrafiltrate line and discarded.
Current membranes, when used to treat acute renal failure associated with MOSF have been associated with incidental improvements in organ function other than the kidneys. However, these membranes remain deficient in the treatment of MOSF because their specific design characteristics prevent them from removing TM in the upper molecular weight range of recognized TM.
The prior art remains deficient in the lack of effective methods of treating toxic mediator-related disease by hemofiltration. The present invention fulfills this long-standing need and desire in this art.